Inflammatory bowel disorders or diseases (IBD) encompass a spectrum of overlapping clinical diseases that appear to lack a common etiology. IBD, however, are characterized by chronic inflammation at various sites in the gastrointestinal (GI) tract. Illustrative IBD are regional enteritis (or Crohn's disease), idiopathic ulcerative colitis, idiopathic proctocolitis, and infectious colitis. Most hypotheses regarding the pathogenesis of IBD concern the implication of immunologic, infectious, and dietary factors.
Colorectal cancer is the most common visceral cancer in the United States. The colorectal cancer progresses through clinically recognizable stages from normal mucosa through enlarging and increasingly dyplastic polyps to carcinoma. The precursor relationship of colorectal adenomatous polyps to carcinoma and the high prevalence of adenomas make them an attractive target in chemoprevention trials. Furthermore, endoscopic or surgical removal of polyps does not change the pathogenetic milieu responsible for their growth and development. The recurrence rate for colorectal adenomas ranges from 20-60% by two years. Patients who have undergone surgical resection of a primary colorectal cancer have also been shown to be at high risk of developing metachronous adenomas. Chemoprevention by pharmacologic intervention remains to be established in clinical practice, and there is a continuing need to develop new chemopreventive treatments for colorectal adenomas.
6-mercaptopurine (6MP) and its prodrug azathioprine (AZA) have been used in the treatment of inflammatory bowel disease (IBD) for over 25 years. Multiple controlled trials and a recent meta-analysis support the efficacy of 6MP and AZA in Crohn's disease. See, J. M. T. Willoughby et al., Lancet, ii 944 (1971); J. L. Rosenberg et al., Dig. Dis., 20, 721 (1975). Several controlled trials support the use of AZA in ulcerative colitis, the most recent by Hawthorne and colleagues, in Brit. Med. J., 305, 20 (1992). Both azathioprine and 6-mercaptopurine have also demonstrated anti-tumor activity against a wide variety of transplantable rodent tumors and against hematologic malignancies in man. However, use of 6MP and AZA has been limited by concerns about their toxicities. Dose-related leukopenia is seen in 2-5% of patients treated long-term with 6MP or AZA for IBD. See, for example, D. H. Present et al., Am. Int. Med., 111, 641 (1989); W. R. Connell et al., Gut, 34, 1081 (1993).
Therefore, a need exits for effective, nontoxic therapies for IBD. Furthermore, there is also a need for new chemopreventative treatments for colorectal adenomas.